Danger-Associated Molecular Patterns Derived From the Extracellular Matrix Provide Temporal Control of Innate Immunity

Abstract

It is evident that components of the extracellular matrix (ECM) act as danger-associated molecular patterns (DAMPs) through direct interactions with pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) and inflammasomes. Through these interactions, ECM-derived DAMPs autonomously trigger sterile inflammation or prolong pathogen-induced responses through the production of proinflammatory mediators and the recruitment of leukocytes to sites of injury and infection. Recent research, however, suggests that ECM-derived DAMPs are additionally involved in the resolution and fine-tuning of inflammation by orchestrating the production of anti-inflammatory mediators that are required for the resolution of tissue inflammation and the transition to acquired immunity. Thus, in this review, we discuss the current knowledge of the interplay between ECM-derived DAMPs and the innate immune signaling pathways that are activated to provide temporal control of innate immunity.

Keywords: Toll-like receptors (TLRs); biglycan; decorin; extracellular matrix; hyaluronan; inflammasome; inflammation; innate immunity; versican.

Figure 1.

ECM-derived DAMP signaling through the innate immunity receptors. Upon injury, the ECM components HS-binding proteoglycans and SLRPs are cleaved by proteinases and the resulting soluble molecules act as DAMPs. They activate specific receptors on the surface of macrophages or intracellularly and promote inflammation. The soluble SLRPs biglycan and decorin bind to TLR2 and TLR4, aggrecan fragments signal through TLR2, and versican via the TLR2/TLR6/CD14 complex. LMW-HA signals through CD44 and further promotes the TLR4-dependent inflammatory response. These interactions promote downstream signaling, which involves the engagement of MyD88 or TRIF; the activation of NF-kB and p38, ERK MAPKs; and the expression of the proinflammatory cytokines and chemokines. Consequently, these mediators attract neutrophils, macrophages, B cells, and T cells to the site of injury. In addition, soluble biglycan clusters TLR2/4 with P2X₇ and modulates the NLRP3 inflammasome. On the contrary, LMW-HA activates the NLPR3 inflammasome via CD44. Thus, biglycan and LMW-HA activate caspase-1, which cleaves pro-IL-1β into mature IL-1β. Abbreviations: ECM, extracellular matrix; DAMPs, danger-associated molecular patterns; HS, heparan sulfate; SLRP, small leucine-rich proteoglycan; TLR, Toll-like receptor; CD, cluster of differentiation; LMW-HA, low-molecular-weight hyaluronan; MyD88, myeloid differentiation primary response gene 88; TRIF, TIR-domain–containing adaptor-inducing interferon-β; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; ERK, extracellular signal–regulated kinase; MAPKs, mitogen-activated protein kinases; NLRP3, NOD-like receptor pyrin domain–containing 3; IL, interleukin; HA, hyaluronan; TNF, tumor necrosis factor; CCL, chemokine (C–C motif) ligand; CXCL, chemokine (C–X–C motif) ligand.